title: Inducible nitric oxide synthase is involved in endothelial dysfunction of mesenteric small arteries from hypothyroid rats.
abstract: The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T(4) replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T(4) replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability.
authors.affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy. a.virdis@med.unipi.it
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Antonio
authors.initials: A
authors.lastname: Polini
authors.forename: Elena
authors.initials: E
authors.lastname: Daghini
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.forename: Narcisa
authors.initials: N
authors.lastname: Ghisu
authors.forename: Daniele
authors.initials: D
authors.lastname: Versari
authors.forename: Angela
authors.initials: A
authors.lastname: Dardano
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Fabio
authors.initials: F
authors.lastname: Monzani
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology*; D008713:Methimazole; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013974:Thyroxine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D008713:Methimazole; D000493:Allopurinol; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D001205:Ascorbic Acid; D013974:Thyroxine; D019331:NG-Nitroarginine Methyl Ester